Low-concentration 12-trans β-selective glycosylation strategy and its applications in oligosaccharide synthesis

Article abstract of DOI:10.1002/chem.200901119

This study develops an operationally easy, efficient, and general 1,2-trans β-selective glycosylation reaction that proceeds in the absence of a C2 acyl function. This process employs chemically stable thioglycosyl donors and low substrate concentrations to achieve excellent β-selectivities in glycosylation reactions. This method is widely applicable to a range of glycosyl substrates irrespective of their structures and hydroxyl-protecting functions. This low-concentration 1,2-trans β-selective glycosylation in carbohydrate chemistry removes the restriction of using highly reactive thioglycosides to construct 1,2-trans β-glycosidic bonds. This is beneficial to the design of new strategies for oligosaccharide synthesis, as illustrated in the preparation of the biologically relevant β-(1-6)-glucan trisaccharide, β-linked Gb₃ and isoGb₃ derivatives.

Full text of DOI:10.1002/chem.200901119

DOI: 10.1002/chem.200901119
Low-Concentration 1,2-trans b-Selective Glycosylation Strategy and Its
Applications in Oligosaccharide Synthesis
Chin-Sheng Chao, Chen-Wei Li, Min-Chun Chen, Shih-Sheng Chang, and
Kwok-Kong Tony Mong*[a]
Dedicated to Professor Hak-Fun Chow
Abstract: This study develops an op-
erationally easy, efficient, and general
1,2-trans b-selective glycosylation reac-
tion that proceeds in the absence of a
C2 acyl function. This process employs
chemically stable thioglycosyl donors
and low substrate concentrations to
achieve excellent b-selectivities in gly-
cosylation reactions. This method is
widely applicable to a range of glycosyl
substrates irrespective of their struc-
tures and hydroxyl-protecting func-
tions. This low-concentration 1,2-trans
b-selective glycosylation in carbohy-
drate chemistry removes the restriction
of using highly reactive thioglycosides
to construct 1,2-trans b-glycosidic
bonds. This is beneficial to the design
of new strategies for oligosaccharide
synthesis, as illustrated in the prepara-
tion of the biologically relevant b-(1!
6)-glucan trisaccharide, b-linked Gb3
and isoGb3 derivatives.
Keywords: carbohydrates · glycosy-
lation · neighboring-group effects ·
stereoselectivity · substrate concen-
tration
Introduction
methods exhibit excellent b-selectivities in glycosylation re-
actions,[8–13] their use in oligosaccharide synthesis remains
scarce.[12c] This is not surprising because most of these meth-
ods suffer from stringent requirements for the structures
and hydroxy-protecting functions of the glycosyl donors.
This lack of flexibility severely limits the scope of the appli-
cation of such methods. Therefore a general, high-yielding
and operationally easy 1,2-trans b-selective glycosylation
that does not invoke neighboring-group participation is
highly desired.
In the light of the discussion above, this study describes,
for the first time, the low-concentration 1,2-trans b-selective
glycosylation process. This method employs easily available
and stable thioglycosides as glycosyl donors for glycosylation
and does not require any C2 participating groups or the use
of special anomeric functions. This study also demonstrates
the proposed glycosylation method in the facile preparation
of b-(1!6)-glucan trisaccharide,[14] Gb3,[15] and isoGb3 deriv-
atives.[16]
Though researchers developed the first glycosylation more
than a century ago, the seamless union of the glycosyl donor
and acceptor in O-glycosidic bond formation remains a for-
midable challenge.[1] A point in case is the construction of
1,2-trans b-glycosidic bonds, which have long been dominat-
ed by the C2 neighboring-group participation strategy.[2] Be-
cause of the participation mechanism, this strategy occasion-
ally suffers from side effects such as orthoester formation,[3]
C2 acyl migration to the hydroxy function,[4] and aglycon
transfer reaction.[4b,5] Under these circumstances, the glyco-
sylation yield is reduced. These issues can be alleviated by
employing benzoyl[6] and pivaloyl functions.[7] An alternative
approach to address this problem is to use 1,2-trans b-selec-
tive glycosylation methods, which do not need the C2 acyl
functions. Though researchers have developed various 1,2-
trans b-selective glycosylation methods and some of these
[a] C.-S. Chao, C.-W. Li, M.-C. Chen, S.-S. Chang, K.-K. T. Mong
Department of Applied Chemistry, National Chiao Tung University
Taiwan, ROC, 1001, Ta Hsueh Road, Hsinchu, 300 (Taiwan)
Fax : (+886)3572-3764
Results and Discussion
Invention of the low-concentration 1,2-trans b-selective gly-
cosylation: In an experiment investigating the nitrile solvent
effect on the stereochemical outcomes of glycosylation,
E-mail: tmong@mail.nctu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901119.
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FULL PAPER
Table 2. Concentration of glycosyl donor and acceptor used in routine
glycosylations.
commercially available galactopyranose acceptor 2 was cou-
pled with 2,3,4-tri-O-benzyl-6-O-levulinoyl b-d-thiogalacto-
pyranoside (1)[17] in CH2Cl2 (solvent A), 1:3 CH2Cl2–CH3CN
(solvent B) and 1:3 CH2Cl2–EtCN (solvent C; Scheme 1 and
Table 1). N-Iodosuccinimide and trimethylsilyl trifluorome-
thanesulfonate were employed as promoters for the activa-
tion of thioglycoside.[18]
Entry Donor [mm] Acceptor [mm] Solvent
Reference
[8a]
[11e]
[22]
[7d]
[9b]
[23]
[12]
1
2
3
4
5
6
7
70
66
220
100
27
75
73
170
150
80
CH2Cl2 or CH3CN
EtCN
CH2Cl2 or CH3CN
CH2Cl2
CH2Cl2–CH3CN
EtCN
CH2Cl2
64
150
32
195
concentration effect on a-selective glycosylation has been
reported, there have been no empirical studies concerning
the effect of substrate concentration on b-selective glycosy-
lation.[25] This lack in the literature motivated the current
study to investigate this unexplored area.
Thus, this study repeated glycosylations of 2 with 1 at dif-
ferent substrate concentrations. All glycosylations were
completed cleanly within 15–20 min. This fast glycosylation
can be attributed to the absence of the disarming C2 acyl
function.[26] Interestingly, a decrease in substrate concentra-
tion accompanies an increase in the formation of the b-
anomer. To be specific, when the concentrations of 1 de-
creased from 240 to 12 mm in 1:3 CH2Cl2–CH3CN mixture
(solvent B), the a/b–anomeric ratios of 3 increased from 1:6
to 1:13 (Table 1, entries 2–5). Further improvement in the b-
selectivity of glycosylation was achieved by simply lowering
the reaction temperature to ꢀ708C, which produced a 1:19
a/b-anomeric ratio (Table 1, entry 6). Considering that the
eutectic temperature of the 1:3 CH2Cl2–CH3CN solvent mix-
ture (ca. ꢀ728C) is close to the reaction temperature
(ꢀ708C), the reaction solutions may freeze.[27] Therefore,
this study repeated the glycosylation reaction in 1:2:1
CH2Cl2–CH3CN/EtCN mixture (solvent D),[28] which to our
delight, did not erode the b selectivity observed in glycosyla-
tion (Table 1, entry 12).
In typical glycosylation reactions, reaction promoters are
added to a mixture of glycosyl donor and acceptors. Schmidt
and Toepfer and the others adopted an inverse addition pro-
cedure in which glycosyl donor is added to a mixture of ac-
ceptor and promoters.[29a] It was reasoned that adding a mix-
ture of donor and acceptor to promoters should presumably
provide lower initial substrate concentrations, which may
further improve the b-selectivity in glycosylation. To this
end, a mixture of donor 1 and acceptor 2 was added to the
promoters over 30 minutes at ꢀ708C, however, an improve-
ment in b-selectivity was not observed (Table 1, entry 12).
This result is different from subsequent cases.
Scheme 1. Glycosylations of galactopyranose acceptor 2 with thiogalacto-
pyranoside 1.
Table 1. Glycosylations of galactopyranose acceptor 2 with thiogalacto-
pyranosyl donor 1 under different reaction conditions.
Entry
[1] mm
[2] mm
Solvent[a]
T [8C]
Yield [%] (a/b)[b]
1
2
3
4
5
6
7
8
120
240
120
60
12
12
120
240
120
60
12
12
100
120
100
50
10
10
100
120
100
50
10
10
A
B
B
B
B
B
A
C
C
C
ꢀ55
ꢀ55
ꢀ55
ꢀ55
ꢀ55
ꢀ70
ꢀ75
ꢀ75
ꢀ75
ꢀ75
ꢀ75
ꢀ70
ꢀ70
75 (1:1.6)
83 (1: 6)
80 (1:9)
84 (1:10)
83 (1:13)
84 (1:19)
78 (1:4)
75 (1: 6)
81 (1:9)
81 (1:12)
70 (1:16)
81 (1:19)
81 (1:19)
9
10
11
12
13
C
D
12
10
D[c]
[a] Solvent system: A=CH2Cl2; B=1:3 v/v CH2Cl2–CH3CN; C=1:3 v/v
CH2Cl2–EtCN and D=1:2:1 v/v CH2Cl2–CH3CN–EtCN. [b] a/b Anomer-
ic ratio was determined by HPLC analysis of crude product mixture.
[c] Inverse addition of 1 and 2 to NIS and TMSOTf in 1:2:1 CH2Cl2–
CH3CN–EtCN solution at ꢀ708C. Bn=benzyl, Lev=levulinoyl,
TMSOTf=trimethylsilyltriflate, Tol=toluene.
As expected, glycosylations in both the CH2Cl2–CH3CN
and CH2Cl2–EtCN solvent mixture afforded a 1:9 a/b–
anomeric ratio of glycosylation product 3 based on the pre-
sumably nitrile solvent effect.[12b–d] However, this level of b-
selectivity in glycosylation is insufficient for state-of-the art
sequential glycosylation technologies, including the automat-
ed solid phase synthesis, various one-pot glycosylation strat-
egies, and others.[1c,19–21] These technologies demand highly
efficient couplings in each single step. A review of the litera-
ture revealed that electrochemical glycosylations in diluted
solutions (10 mm of thioglycoside) yield nearly exclusive for-
mation of b-glycosylating products.[22] On the other hand,
routine glycosylations are normally performed at a glycosyl
substrate concentration between 30 and 100 mm (Table 2).[8
Scope and limitations of the low-concentration 1,2-trans b-
selective glycosylation: After exploring the low-concentra-
tion 1,2-trans b-selective glycosylation process, this study
next examined the scope and limitations of this method.
Thioglycosides 4–12 were employed as glycosyl donors for
the glycosylation of acceptors 2 and 13 (Scheme 2 and
Table 3).[17] For comparison, the glycosylation reaction was
d,9a,12e,23,24]
Though a preliminary study concerned with the
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K.-K. Tony Mong et al.
Encouraged by these preliminary results, we extended the
scope of this study to more diverse glycosyl substrates. Thus
b-d-thiolactosides (23, 24), 2-azido-2-deoxy-b-d-thiogluco-
pyranoside 25, and b-d-thiomannopyranoside 26 prepared
by standard methods were used for glycosylation of accept-
ors (Scheme 3 and Table 4).[17,31] With the exception of gly-
Scheme 2. Thioglycosyl donors 4–12 for the study of low-concentration
1,2-trans b-selective glycosylation.
Table 3. Results of the low-concentration 1,2-trans b-selective glycosyla-
tions of acceptors 2 and 3 with different thioglycosyl donors 4–12.
Entry
12 mm
donor
10 mm
acceptor
Product
Yield [%]
(a/b)[a]
Yield [%]
ACHTUNGTRENNUNG
(a/b)[a,b]
U
1
2
3
4
5
6
7
8
4
5
6
7
8
9
9
10
11
12
2
2
2
2
2
2
2
2
14
15
16
17
18
19
19
20
21
22
85 (1:33)[c]
83 (1:2)
67 (1:2)
73 (1:1)
77 (1:8)
85 (1:2.5)
75 (1:6)
not done
75 (1:6)
80 (1:4)
88 (1:4)
70 (1:ꢁ49)[c]
77 (1:ꢁ49)[d]
83 (1:19)[d]
83 (1:ꢁ49)[c]
75 (1:9)[c]
Scheme 3. Glycosyl donors 23–26 and acceptors 27–32 for the extended
investigation of the low-concentration 1,2-trans b-selective glycosylation.
83 (1:19)[c,e]
75 (b only)[c]
80 (1:49)[c]
9
10
13
13
Table 4. Results of the extended investigation of low-concentration 1,2-
85 (1:ꢁ49)[c]
trans b-selective glycosylation.
[a] a/b-Anomeric ratio was determined by HPLC analysis. [b] Glycosyla-
tions in CH2Cl2 with 120 mm of thioglycosyl donor and 100 mm of accept-
or at ꢀ558C. [d] Glycosylations in 1:3 v/v CH2Cl2–CH3CN with 12 mm of
thioglycosyl donor and 10 mm of acceptor at ꢀ708C. [c] Glycosylations in
1:2:1 v/v CH2Cl2–CH3CN–EtCN with 12 mm of thioglycosyl donor and
10 mm of acceptor at ꢀ708C. [e] For this particular reaction, 6 mm of thio-
glycosyl donor 9 and 5 mm of acceptor 2 were used.
Entry
12 mm
10 mm
Product
Yield [%]
(a/b)[a,c]
Yield [%]
ACHTUNGTRENNUNG
(a/b)[b,c]
donor
acceptor
U
1
2
3
4
5
6
7
8
9
1
1
1
6
1
8
23
24
25
26
27
28
29
30
31
32
13
13
13
2
33
34
35
36
37
38
39
40
41
42
65 (1:49)
64 (1:1)
60 (1:8)
not done
80 (1:2)
75 (19:1)
78 (1:7)
77 (1:3)
not done
not done
not done
63 (1:ꢁ49)
60 (b only)
83 (1:ꢁ49)
73 (1:ꢁ49)
77 (1:32)
80 (b only)[d]
83 (1:ꢁ49)[d]
60 (1:ꢁ49)
85 (3:1)
performed under both low-concentration 1,2-trans b-selec-
tive and conventional glycosylation conditions.
Remarkably, the low-concentration b-selective glycosyla-
tion for thioglycosyl donors in the d-gluco (6, 7, 8), d-galac-
to (4, 5, 9, and 12), d-lacto (10), and l-fuco (11) series pro-
duced excellent b-selectivities and the resulting a/b-anome-
ric ratios ranged from 1:9 to 1:ꢁ49. An additional advant-
age of this method is its tolerance to different hydroxy-pro-
tecting functions, as evidenced by the glycosylation reactions
with thiogalactopyranosides 1, 4, 5, 9, and 12 (Table 1 and
Table 3, entries 1,2, 6–7, and 10). Although 4,6-O-benzyli-
dene thiogalactopyranosyl acetal 9 is generally considered
as an a-directing glycosyl donor,[30] the glycosylation of ac-
ceptor 2 with 9 under low-concentration conditions resulted
in the predominant formation of the b-anomer (Table 3, en-
tries 6, 7).
10
[a] Glycosylation in 1:2:1 v/v CH2Cl2–CH3CN–EtCN mixture at ꢀ708C
with 12 mm of thioglycosyl donor and 10 mm of acceptor. [b] Glycosy-
lation in CH2Cl2 at ꢀ558C with 120 mm of thioglycosyl donor and 100 mm
of acceptor. [c] a/b-Anomeric ratio was determined by HPLC analysis.
[d] Two equivalents of acceptor was used to prevent self-condensation.
cosylation with thiomannopyranoside 26, all reactions pro-
duced excellent b-selectivities in the glycosylation reactions,
with a/b-anomeric ratios ranging from 1:32 to b-exclusive.
The glycosylations of acceptors 27, 28, 29, and 32 are typical
examples (Table 4, entries 1–3 and 6). Though all these ac-
ceptors contain the sterically hindered hydroxyl function,
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Applications of Selective Glycosylation in Oligosaccharide Synthesis
FULL PAPER
the corresponding glycosylations yielded b-anomers as the
sole isomeric products.[32] These results reveal the synthetic
utility of this novel method because disaccharides 36 and 38
constitute the essential components in the cell wall of Sac-
charomyces cerevisiae[14] and the type-2 backbone in blood-
group determinants, respectively.[33]
Figure 1 presents a dramatic set of data for the glycosyla-
tions of Na-Fmoc serine allyl ester 31 (Fmoc=9-fluorenyl-
methoxycarbonyl) with thiogalactopyranoside 1. The glyco-
Figure 2. The plot of the percentage of a anomer of 3 against the concen-
trations (mm) of thiogalactopyranoside 1.
After confirming the importance of thioglycoside concen-
tration, we next examine the effect of the anomeric configu-
ration of the glycosyl donor on low-concentration 1,2-trans
b-selective glycosylation. Poletti and co-workers reported
that the anomeric configuration of thioglycosyl donors af-
fects the stereoselectivities of glycosylation.[32] However,
these results differ from those observed for glycosylations
with glycosyl imidate[12d] or phosphite donors.[12f] To clarify
the role of anomeric configuration of thioglycoside, a-thio-
galactopyranoside 1a was prepared and used for the glyco-
sylation of 2. No significant change in b-selectivity was ob-
served (Scheme 4). Empirically, anomeric configuration of
Figure 1. HPLC traces for glycosylations of N-Fmoc serine ester 31 with
thiogalactopyranoside 1 under different conditions: a) conventional gly-
cosylation conditions in CH2Cl2 and b) conventional glycosylation condi-
tions in 1:2:1 v/v CH2Cl2–CH3CN–EtCN mixture; and c) low-concentra-
tion 1,2-trans b-selective glycosylation conditions in 1:2:1 v/v CH2Cl2–
CH3CN–EtCN mixture.
sylation of aglycon acceptor 31 with thioglycoside 1 in
CH2Cl2 under conventional conditions produced the a-
anomer of 37 as the major isomer (Figure 1, HPLC trace a).
Even when the same glycosylation was performed in a 1:2:1
CH2Cl2/CH3CN/EtCN mixture, only marginal b-selectivity in
glycosylation was observed under conventional glycosylation
conditions (Figure 1, HPLC trace b). In sharp contrast, the
application of low-concentration 1,2-trans b-selective glyco-
sylation led to nearly exclusive formation of the b-anomer
(Figure 1, HPLC trace c).
Scheme 4. Low-concentration 1,2-trans b-selective glycosylation of galac-
topyranose acceptor 2 with a-thiogalactopyranoside 1a.
thioglycoside is immaterial to b-stereoselectivity in glycosy-
lation, which implicates that the stereochemical course of
low-concentration 1,2-trans b-selective glycosylation proba-
bly involves a common intermediate.
Mechanistic insight of the low-concentration 1,2-trans b-se-
lective glycosylation: To gain insight into the mechanisms of
the present glycosylation, this study further investigates
which particular substrate concentration is most closely re-
lated to the b-selectivity observed. Thus, 10 mm of acceptor
2 was glycosylated with different concentrations of thioga-
lactopyranoside 1 and N-iodosuccinimide (NIS; concentra-
tion range of 12–60 mm). Plotting the percentage of the a-
anomer of 3 obtained against the concentration of donor 1
revealed a concentration-dependent relationship (Figure 2).
Meanwhile, no significant change in b-selectivity was noted
for glycosylation of 60 mm of acceptor 2 with 10 mm of
donor 1. This finding confirmed the substantial role of low
thioglycoside concentration that is present in 1,2-trans b-se-
lective glycosylation.
Based on experimental data and literature review, the
aforementioned intermediate should be the free oxocarbeni-
um ion arising from activation of thioglycoside,[12b,c,g] and
thereof a mechanism is proposed as shown in Scheme 5. Ac-
tivation of thioglycoside gives rise to free oxocarbenium ion.
Owing to the high dielectric constant of the CH2Cl2/nitrile
solvent mixture,[34] the formation a-glycosyl triflate is unlike-
ly.[35] Instead, the free oxocarbenium ion reacts with the hy-
droxy acceptor to produce a a/b-anomeric mixture. Alter-
nately, it might couple with the nitrile solvent molecule to
generate the kinetically favoured a-glycosyl nitrilium.[12,36,37]
Further SN2-like reaction of the a-glycosyl nitrilium with the
acceptor leads to the formation of the b-anomer.
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K.-K. Tony Mong et al.
Scheme 5. Proposed mechanism of the low-concentration1,2-trans b-se-
lective glycosylation.
Scheme 6. Stepwise synthesis of b-(1!6)-glucan trisaccharide 44. i) See
Table 3, entry 4 for conditions.
Apparently, low substrate concentrations, low reaction
temperature, and appropriate CH2Cl2/nitrile solvent mixture
act synchronously to enhance a-glycosyl nitrilium formation,
which depletes the free oxocarbenium ion through an equi-
librium process. The argument agrees with that proposed by
Crich and co-workers in b-selective rhamnosylation.[10b]
However, attempts to detect the a-glycosyl nitrilium with
NMR spectroscopy have so far been unsuccessful owing to
substantial peak broadening in low-temperature NMR spec-
troscopy (below approximately ꢀ508C).[38] Additional exper-
imentations are currently underway to address this issue.
spacer; with such a spacer, further chemical elaboration is
possible. Conventional preparation of Gb3 and isoGb3 deriv-
atives involves construction of perbenzoyl lactoside, which
undergoes further protection–deprotection reactions and ad-
ditional glycosylation to furnish the target.[39] It was envis-
aged that the application of low-concentration 1,2-trans b-
selective glycosylation should enable the development of a
reverse sequential glycosylation strategy for the preparation
of Gb3 and isoGb3 derivatives.
Acceptor 13 was chemoselectively glycosylated with thio-
lactosides 23 and 24 with low-concentration b-selective gly-
cosylations to afford the corresponding b-linked lactoside
acceptors (Scheme 7a and b). No traces of self-condensation
products were detected, which is attributed to the higher re-
activity of the hydroxy function in aglycon acceptor 13 com-
pared with the hindered hydroxy functions in thiolactosides
23 and 24. Without isolation of the glycosylation product
and deprotection of the protected hydroxy function, the
crude b-linked lactosides was used directly as acceptors for
glycosylation with thiogalactopyranoside 45 in CH2Cl2. This
reverse sequential glycosylation strategy produces the pro-
tected Gb3 and isoGb3 derivatives 46 and 48 in high overall
yields (75% for 46 and 70% for 48 based on two glycosyla-
tion steps) with extremely good anomeric purities, as proven
in the 13C NMR spectra in Figure 3. Subsequent standard
global deprotection reactions afforded Gb3 and isoGb3 tri-
saccharide derivatives, 47 and 49.
Synthetic utilities of the low-concentration 1,2-trans b-selec-
tive glycosylation: Regarding synthetic utility, the direct
impact of low-concentration 1,2-trans b-selective glycosyla-
tion is to provide an alternative 1,2-trans b-selective glycosy-
lation strategy. This strategy does not require a C2-participa-
tion protecting function and therefore allows the use of
more-reactive thioglycosyl donors in the formation of 1,2-
trans b-glycosidic bonds. This is useful in the design of new
strategies in oligosaccharide synthesis as the following exam-
ples illustrate.
b-(1!6)-Glucan is the essential fungal-specific carbohy-
drate component found in the cell wall of Saccharomyces
cerevisiae.[14] Previous attempts to synthesize b-(1!6)-
glucan trisaccharide without a C2 acyl function have been
reported, resulting in a 1:9 a/b-anomeric mixture.[13] Low-
concentration 1,2-trans b-selective glycosylation might
enable a highly stereoselective synthesis of b-(1!6)-glucan
trisaccharide (Scheme 6). The glycosylation of methyl a-d-
glucopyranoside 30 with thiogalactopyranoside 6 produced
disaccharide glycoside 36 as mentioned above, and the treat-
ment of 36 with standard Zemplꢁn deacylation produced
disaccharide acceptor 43. The glycosylation of 43 with donor
6 afforded protected b-(1!6)-glucan trisaccharide 44 with a
high yield and excellent b-anomeric purity.
Conclusions
The study explores, for the first time, the effect of substrate
concentrations on 1,2-trans b-selective glycosylation. This
study proposes a low-concentration 1,2-trans b-selective gly-
cosylation method, which is applicable to a wide range of
glycosyl substrates and enables the development of new syn-
thetic routes for biologically relevant b-(1!6)-glucan trisac-
charide, Gb3 and isoGb3. As b-linked glycosidic bonds occur
frequently in natural oligosaccharides, this new b-selective
glycosylation strategy should prove useful for their prepara-
tion.
Further to the stepwise synthesis, the low-concentration
1,2-trans b-selective glycosylation is useful for sequential
glycosylation, as illustrated in the preparation of globotriao-
sylceramide (Gb3) and isoGb3 derivatives. Both the trisac-
charide derivatives carry the b-linked functionalizable
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Applications of Selective Glycosylation in Oligosaccharide Synthesis
FULL PAPER
Experimental Section
General: Reagent-grade chemicals were purchased and used without fur-
ther purification. N,N-dimethylformamide (DMF) was distilled over cal-
cium hydride and stocked with flame-dried molecular sieves(MS) under
N2. The progress of reactions was monitored by thin-layer chromatogra-
phy on silica gel 60 F-254 plate and visualized under UV illumination
and by staining with acidic ceric ammonium molybdate or p-anisalde-
hyde. Optical rotations were measured with polarimeter at 278C. HPLC
analysis was performed over Mightysil column with elution of EtOAc/
hexane mixture at a 1.2 mLminꢀ1 flow rate by the gradient pump (l-
2130) and UV detector (l-2400) from Hitachi. NMR spectra were record-
ed at 300 MHz and 75 MHz spectrometers in
a Brꢂker console or
500 MHz and 125 MHz in a Varian console as specified. The chemical
shift was calibrated against the residual proton signal and the 13C signal
of deuterated chloroform or deuterated methanol. Coupling constants in
1
Hz was calculated from chemical shift of H NMR or spectra.
General procedure for low-concentration 1,2-trans b-selective glycosyla-
tion:
A mixture of thioglycoside (1.2 mol equiv), acceptor (1.0 mo-
l equiv), and flame-dried MS (AW300) were suspended in 1:3 v/v
CH2Cl2–CH3CN or 1:2:1 v/v CH2Cl2–CH3CN–EtCN solvent mixture such
that the final concentrations of thioglycoside and acceptor were 12 and
10 mm, respectively (for particular details see Table S1 in the Supporting
Information). The resulting mixture was stirred at room temperature for
10 min and at ꢀ708C for an additional 20 min under N2, and followed by
the addition of NIS (1.2 mol equiv) and trimethylsilyltriflate (TMSOTf;
0.24 mol equiv). Glycosylation coupling was monitored by TLC with
either EtOAc–hexane or EtOAc–CH2Cl2–hexane mixture as the develop-
ing solvent. Upon completion of glycosylation, a small volume of saturat-
ed NaHCO3 and small lumps of Na2S2O3(s) were added to the mixture,
followed by vigorous stirring until the deep-red color of the reaction mix-
ture turned to pale yellow. Then the MS were removed by filtration over
celite. The filtrate was dried (over MgSO4), filtered, and concentrated for
flash-chromatography purification over silica gel to furnish glycosylation
products for NMR characterization. A small portion of crude reaction
mixture was filtered through a short pad of silica gel (approximately
10 cm) and concentrated for determination of the a/b-anomeric ratio by
HPLC analysis by using conditions as described in the general experi-
mental section. Preparation of glycosyl substrates 1, 4–12, 23–32 for gly-
cosylation studies and NMR spectra of compounds 1, 3--12, 14–49 are
presented in the Supporting Information.
Scheme 7. a) Sequential glycosylation strategy for synthesis of Gb3 deriv-
ative 47 and b) isoGb3 derivative 49. TBAF=tetrabutylammonium fluo-
ride, TMSOTf=trimethylsilyltriflate.
Low-temperature NMR spectroscopy for thiogalactopyranoside (1): Thio-
galactopyranoside 1 (33 mg for 100 mm or 3.3 mg for 10 mm) in a pre-
dried NMR tube was dried under vacuum overnight and then 1:3 v/
v CD2Cl2–CD3CN with 5 vol% EtCN (500 mL) was added under N2. The
resulting mixture was then analyzed
by NMR spectroscopy at a tempera-
ture range of 258C to ꢀ608C (selected
spectra are given in the Supporting In-
formation).
Low-temperature NMR spectroscopy
for NIS-/TMSOTf-activated thiogalac-
topyranoside (1): Thiogalactopyrano-
side 1 (33 mg) in a pre-dried NMR
tube was dried under vacuum
overnight and then 500 mL of 1:3
v/v CD2Cl2–CD3CN (with 25 mL of
EtCN added as internal reference)
was added under N2. The resulting so-
lution was cooled at ꢀ808C bath for
approximately 10 min, followed by the
addition of TMSOTf (2 mL) in CD2Cl2
solution (10 mL). The resulting mixture
was then analyzed by NMR spectros-
copy at temperature range of ꢀ50 to
ꢀ308C (selected spectra for VT-NMR
are given in the Supporting Informa-
tion).
Figure 3. 13C NMR spectra of a) protected Gb3 46 and b) protected isoGb3 48.
Chem. Eur. J. 2009, 15, 10972 – 10982
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10977

K.-K. Tony Mong et al.
1,2:3,4-di-O-isopropylidene-6-O-(2’,3’,4’-tri-O-benzyl-6’-O-levulinoyl-b-d-
galactopyranosyl)-1-a-d-galactopyranose (3): Synthesis of was per-
b-selective glycosylation. 17 (126 mg, 83%) was obtained as colorless oily
liquid. [a]2D7 =ꢀ22.42 (c=0.35, in CHCl3); 1H NMR (300 MHz, CDCl3,
258C, TMS): d=7.46–7.43 (m, 2H; ArH), 7.37–7.27 (m, 13H; ArH), 5.6
(d, J=5.1 Hz, 1H), 5.09–4.99 (m, 2H), 4.86 (d, J=11.7 Hz, 1H), 4.73 (d,
J=11.1 Hz, 1H), 4.67–4.59 (m, 2H), 4.55–4.51 (m, 3H), 4.35 (dd, J=2.4,
5.1 Hz, 1H), 4.26 (dd, J=1.5, 7.8 Hz, 1H), 4.21–4.12 (m, 2H), 3.78 (dd,
J=7.2, 10.2 Hz, 1H), 3.66–3.50 (m, 5H), 2.62–2.54 (m, 2H; CH2 C=O),
2.45–2.25 (m, 2H; CH2C=O), 2.13 (s, 3H; CH3 C=O), 1.53 (s, 3H;
CH3C), 1.48 (s, 3H; CH3C), 1.35 ppm (s, 6H; CH3C); 13C NMR (75 MHz,
CDCl3, 258C, TMS): d=206.6, 172.0, 139.0, 138.9, 138.5, 129.1, 128.71,
128.68, 128.64, 128.3, 128.0, 127.9, 109.8, 109.0, 104.7, 96.8, 81.9, 81.7,
75.4, 74.9, 74.0, 73.7, 71.8, 71.4, 71.2, 70.9, 69.9, 67.9, 38.2, 30.2, 28.3, 26.5,
26.4, 25.4, 24.9 ppm; HRMS (ESI): m/z: calcd for C44H54O13: 790.3564
[M]+; found: 790.3568.
3
formed as per the general procedure of low-concentration 1,2-trans b-se-
lective glycosylation. 3 (128 mg, 84%) was obtained as glassy solid.
[a]2D7 =ꢀ35.34 (c=0.9, in CHCl3); 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=7.50–7.47 (d, J=9.3 Hz, 2H; ArH), 7.46–7.28 (m, 13H; ArH),
5.59 (d, J=4.95 Hz, 1H, H-1), 5.09 (d, J=11.1 Hz, 1H), 4.88 (d, J=
12 Hz, 1H), 4.80–4.75 (m, 2H), 4.68 (d, J=11.4 Hz, 1H), 4.61 (dd, J=
2.4, 7.8 Hz, 1H), 4.45 (d, J=7.8 Hz, 1H), 4.33 (dd, J=2.4, 5.1 Hz, 1H),
4.28–4.22 (m, 2H), 4.18–4.10 (m, 3H; 3.91–3.83 (m, 2H), 3.7 (dd, J=6.9,
9.9 Hz, 1H), 3.58–3.54 (m, 2H), 2.76–2.71 (m, 2H; CH2C=O), 2.53–2.48
(m, 2H; CH2C=O), 2.20 (s, 3H; CH3C=O), 1.52 (s, 3H; CH3C), 1.48 (s,
3H; CH3C), 1.35 (s, 3H; CH3C), 1.34 ppm (s, 3H; CH3C); 13C NMR
(75 MHz, CDCl3, 258C): d=206.9, 172.74, 139.4, 139.0, 138.7, 129.0,
128.9, 128.8, 128.6, 128.5, 128.1, 128.0, 127.8, 109.7, 109.0, 105.1, 96.8,
82.3, 79.3, 75.2, 74.8, 72.3, 71.9, 71.2, 70.9, 7.1, 67.8, 63.5, 38.3, 30.2, 28.2,
1,2:3,4-Di-O-isopropylidene-6-O-(2’-azido-3’,4’,6’-tri-O-benzyl-2’-deoxy-b-
d-glucopyranosyl)-1-a-d-galactopyranose (18): Synthesis of 18 was per-
formed according to the general procedure of low-concentration 1,2-trans
b-selective glycosylation. 18 (114 mg, 83%) was obtained as a colorless
oily liquid. [a]2D7 =ꢀ35.30 (c=1.08, in CHCl3); 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=7.42–7.30 (m, 13H; ArH), 7.22–7.19 (m, 2H;
ArH), 5.6 (d, J=5.1 Hz, 1H), 4.95 (d, J=10.8 Hz, 1H), 4.84 (dd, J=5.7,
10.8 Hz, 1H), 4.67–4.55 (m, 4H), 4.48–4.46 (m, 1H), 4.36 (dd, J=2.4,
4.8 Hz, 1H), 4.32 (dd, J=1.2, 8.1 Hz, 1H), 4.1 (m, 2H), 3.88–3.66 (m,
4H), 3.49–3.45 (m, 3H), 1.59 (s, 3H; CH3C), 1.49 (s, 3H; CH3C), 1.38 (s,
3H; CH3C), 1.37 ppm (s, 3H; CH3C); 13C NMR (75 MHz, CDCl3, 258C):
d=138.49, 138.46, 138.39, 128.88, 128.85, 128.81, 128.47, 128.3, 128.1,
109.7, 109.1, 102.9, 96.7, 83.5, 78.1, 75.9, 75.4, 74.0, 71.7, 71.1, 70.9, 69.2,
68.9, 68.0, 66.8, 26.5, 26.4, 25.4, 24.8 ppm; HRMS (ESI): m/z: calcd for
C39H47N3O10Na: 740.3159 [M+Na]+; found: 740.3154.
26.44, 26.41, 25.5, 24.8 ppm; HRMS (FAB): m/z: calcd for C44H54O13
790.3564 [M]+; found: 790.3561.
:
1,2:3,4-Di-O-isopropylidene-6-O-(4’-O-acetyl-2’,3’,6’-tri-O-benzyl-b-d-gal-
actopy- ranosyl)-1-a-d-galactopyranose (14): Synthesis of 14 was per-
formed as per to the general procedure of low-concentration 1,2-trans b-
selective glycosylation. 14 (120 mg, 85%) was obtained as colorless oil.
[a]2D7 =ꢀ6.31 (c=1.2, in CHCl3); 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=7.50–7.48 (m, 2H; ArH), 7.42–7.28 (m, 13H; ArH), 5.63–5.61
(m, 2H), 5.08 (d, J=11.1 Hz, 1H), 4.8 (d, J=11.4 Hz, 1H), 4.72 (d, J=
11.1 Hz, 1H), 4.64–4.49 (m, 5H), 4.36 (dd, J=2.4, 5.1 Hz, 1H), 4.27 (dd,
J=1.5, 7.8 Hz, 1H), 4.22–4.14 (m, 2H), 3.82–3.73 (m, 2H), 3.68–3.53 (m,
4H), 2.11 (s, 3H; CH3C=O), 1.54 (s, 3H; CH3C), 1.49 (s, 3H; CH3C),
1.36 ppm (s, 6H; CH3C); 13C NMR (75 MHz, CDCl3, 258C): d=170.8,
139.3, 138.4, 138.0, 128.91, 128.9, 128.7, 128.6, 128.52, 128.51, 128.3, 128.1,
127.8, 109.8, 109.0, 105.0, 96.8, 79.4, 79.0, 75.4, 74.1, 72.5, 72.4, 71.9, 71.2,
70.9, 70.4, 68.4, 67.8, 67.3, 26.4, 25.5, 24.9, 21.4 ppm; HRMS (ESI): m/z:
calcd for C41H50O12Na: 757.3194 [M+Na]+; found: 757.3194.
1,2:3,4-Di-O-isopropylidene-6-O-(2’,3’-di-O-benzyl-4’,6’-O-benzylidene-b-
d-galactopyranosyl)-1-a-d-galactopyranose (19): Synthesis of 19 was gen-
erally based on the general procedure of low-concentration 1,2-trans b-
selective glycosylation, but lower substrate concentrations (5 mm of gly-
cosyl acceptor 2 and 6 mm of glycosyl donor 9) were used to obtain a
1:19 a/b anoemric ratio of 19. Disaccharide 19 (110 mg, 83%) was ob-
tained as white amorphous solid. [a]2D7 =ꢀ12.59 (c=1.4, in CHCl3);
1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.62–7.58 (m, 2H, ArH),
7.55–7.52 (m, 2H, ArH), 7.45–7.28 (m, 11H, ArH), 5.62 (d, J=5.1 Hz,
1H; H-1), 5.54 (s, 1H; PhCH), 5.13 (d, J=11.1 Hz, 1H), 4.84–4.77 (m,
3H), 4.63 (dd, J=2.4, 7.8 Hz, 1H), 4.49 (d, J=7.8 Hz, 1H), 4.36 (dd, J=
2.4, 5.1 Hz, 1H), 4.34–4.21 (m, 3H), 4.17–4.13 (m, 2H), 4.04 (dd, J=1.2,
12.3 Hz, 1H), 3.91 (dd, J=7.5, 9.6 Hz, 1H), 3.77 (dd, J=7.2, 10.5 Hz,
1H), 3.60 (dd, J=3.6, 9.6 Hz, 1H), 3.32 (s, 1H), 1.55 (s, 3H; CH3C), 1.50
(s, 3H; CH3C), 1.37 ppm (s, 6H; CH3C); 13C NMR (75 MHz, CDCl3,
258C, TMS): d=139.6, 138.9, 138.3, 129.3, 128.9, 128.8, 128.7, 128.6, 128.5,
128.2, 128.1, 127.8, 126.9, 109.7, 109.1, 104.8, 101.6, 96.8, 79.3, 78.6, 75.4,
74.6, 72.5, 71.9, 71.2, 70.9, 69.9, 69.6, 67.8, 66.9, 26.5, 26.4, 25.5, 24.9 ppm;
HRMS (ESI): m/z: calcd for C39H46O11Na: 713.2932 [M+Na]+; found:
713.2933.
1,2:3,4-Di-O-isopropylidene-6-O-(2’,6’-di-O-benzyl-3’,4’-di-O-methoxycar-
bonyl-b-d-galactopyranosyl)-1-a-d-galactopyranose (15): Synthesis of 15
was performed as described in the general procedure for low-concentra-
tion 1,2-trans b-selective glycosylation. 15 (98 mg, 71%) was obtained as
light-yellow oily liquid. [a]2D7 =ꢀ8.39 (c=0.53 , in CHCl3); 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=7.39–7.26 (m, 10H; ArH), 5.57 (d, J=
5.1 Hz, 1H; H-1), 5.37 (d, J=3.0 Hz, 1H), 5.02 (d, J=11.4 Hz, 1H), 4.85
(dd, J=3.3, 10.2 Hz, 1H), 4.65–4.47 (m, 5H), 4.33 (dd, J=2.4, 4.8 Hz,
1H), 4.23 (dd, J=1.8, 8.1 Hz,1H), 4.16–4.07 (m, 2H), 3.82 (s, 3H), 3.80–
3.58 (m, 8H), 1.52 (s, 3H; CH3C), 1.46 (s, 3H; CH3C), 1.33 ppm (s, 6H;
CH3C); 13C NMR (75 MHz, CDCl3, 258C): d=155.9, 155.3, 138.9, 138.1,
128.8, 128.5, 128.4, 128.22, 128.2, 127.8, 109.8, 109.0, 104.5, 96.8, 76.9,
75.1, 74.0, 72.1, 71.9, 71.8, 71.1, 70.9, 0.1, 68.0, 67.8, 55.53, 55.51, 26.43,
26.38, 25.4, 24.8 ppm; HRMS (ESI): m/z: calcd C36H46O15Na: 741.2729
[M+Na]+; found: 741.2729.
1,2:3,4-Di-O-isopropylidene-6-O-(2’,3’,4’-tri-O-benzyl-6’-O-levulinoyl-b-
d-gluco- pyranosyl)-1-a-d-galactopyranose (16): Synthesis of 16 was pre-
pared according to the general procedure of low-concentration 1,2-trans
b-selective glycosylation. 16 (117 mg, 77%) was obtained as white glassy
solid. [a]2D7 =ꢀ14.80 (c=0.84, in CHCl3); 1H NMR (300 MHz, CDCl3,
258C, TMS): d=7.46–7.42 (m, 2H; ArH), 7.36–7.25 (m, 13H; ArH), 5.59
(d, J=5.1 Hz, 1H; H-1), 5.08 (d, J=11.1 Hz, 1H), 5.00 (d, J=10.8 Hz,
1H), 4.88 (d, J=10.8 Hz, 1H), 4.81 (d, J=11.1 Hz, 1H), 4.74 (d, J=
11.1 Hz, 1H), 4.63–4.56 (m, 2H), 4.49 (d, J=7.8 Hz, 1H), 4.35–4.25 (m,
4H), 4.15–4.10 (m, 2H), 3.77–3.65 (m, 2H), 3.54–3.44 (m, 3H), 2.78–2.72
(m, 2H; CH2C=O), 2.62–2.58 (m, 2H; CH2C=O), 2.20 (s, 3H; CH3C=O),
1.52 (s, 3H; CH3C), 1.48 (s, 3H; CH3C), 1.35 (s, 3H; CH3C), 1.33 ppm (s,
3H; CH3C); 13C NMR (75 MHz, CDCl3, 258C): d=206.8, 172.9, 139.0,
138.9, 138.2, 129.0, 128.9, 128.8, 128.6, 128.5, 128.3, 128.0, 127.9, 109.8,
108.9, 104.9, 96.8, 84.9, 81.9, 77.8, 77.6, 76.4, 75.4, 74.8, 73.2, 71.2, 71.8,
71.1, 70.8, 70.2, 67.7, 63.7, 38.3, 30.3, 28.3, 26.43, 26.4, 25.4, 24.8 ppm;
HRMS (FAB): m/z: calcd for C44H54O13: 790.3564 [M]+; found: 790.3578.
1,2:3,4-Di-O-isopropylidene-6-O-[2’,3’,6’-tri-O-benzyl-4’-O-(2”,3”,4”,6”-
tetra-O-benzyl-b-d-galactopyranosyl)-b-d-glucopyranosyl)]-1-a-d-galacto-
pyranose (20): Synthesis of 20 was performed according to the general
procedure of low-concentration 1,2-trans b-selective glycosylation. 20
(175 mg, 75%) was obtained as a colorless oily liquid. [a]2D7 =ꢀ15.38 (c=
2.07, in CHCl3); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.49–7.18
(m, 35H; ArH), 5.62 (d, J=5.1 Hz, 1H), 5.08–5.00 (m, 3H), 4.84–4.74
(m, 7H), 4.64–4.57 (m, 3H), 4.50–4.44 (m, 2H), 4.41–4.35 (m, 2H), 4.31–
4.27 (m, 2H), 4.21–4.17 (m, 2H), 4.03–3.96 (m, 2H), 3.88–3.72 (m, 4H),
3.63–3.56 (m, 2H), 3.49–3.37 (m, 5H), 1.55 (s, 3H; CH3C), 1.51 (s, 3H;
CH3C), 1.37 ppm (s, 6H; CH3); 13C NMR (75 MHz, CDCl3, 258C): d=
139.6, 139.5, 139.4, 139.2, 139.0, 138.8, 138.5, 128.9, 128.81, 128.79, 128.68,
128.66, 128.52, 128.38, 128.30, 128.17, 128.11, 127.96, 127.86, 127.80,
127.46, 109.76, 109.02, 104.80, 103.17, 83.18, 82.98, 81.68, 80.40, 77.71,
75.79, 75.70, 75.51, 75.13, 74.97, 74.02, 73.83, 73.52, 73.36, 72.97, 71.83,
71.18, 70.93, 69.91, 68.62, 68.51, 67.74, 26.50, 26.45, 25.49, 24.88 ppm;
1,2:3,4-Di-O-isopropylidene-6-O-(2’,3’,6’-tri-O-benzyl-4’-O-levulinoyl-b-
d-glucopyranosyl)-1-a-d-galactopyranose (17): Synthesis of 17 was pre-
pared according to the general procedure of low-concentration 1,2-trans
HRMS (FAB): m/z: calcd for C73H82O16
:
1214.5603 [M]+; found:
1214.5608.
10978
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 10972 – 10982

Applications of Selective Glycosylation in Oligosaccharide Synthesis
FULL PAPER
6-Chlorohexyl 2,3,4-tri-O-benzyl-1-b-l-fucopyranoside (21): Synthesis of
21 was performed according to the general procedure of low-concentra-
tion 1,2-trans b-selective glycosylation. 21 (93 mg, 80%) was obtained as
colorless oily liquid. [a]2D7 =+5.52 (c=0.32, in CHCl3); 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=7.41–7.27 (m, 15H; ArH), 5.01 (d, J=
11.7 Hz, 1H), 4.96 (d, J=11.1 Hz, 1H), 4.85–4.47 (m, 4H), 4.34 (d, J=
7.5 Hz, 1H), 3.97 (dt, J=6.3, 9.6 Hz, 1H), 3.83 (dd, J=7.8, 9.6 Hz, 1H),
3.59–3.44 (m, 6H), 1.81–1.64 (m, 4H; CH2), 1.51–1.37 (m, 4H; CH2),
1.20 ppm (d, J=6.3 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3, 258C): d=
139.33, 139.08, 139.02, 128.95, 128.79, 128.68, 128.53, 128.43, 127.97,
127.91, 104.2, 82.97, 79.89, 77.69, 76.66, 75.49, 74.34, 73.58, 70.69, 69.99,
45.5, 32.95, 30.0, 27.1, 25.9 ppm; HRMS (ESI): m/z: calcd for
C33H41ClO5Na: 575.2540 [M+Na]+; found: 575.2535.
138.8, 135.6, 135.5, 128.77, 128.76, 128.67, 128.6, 128.4, 128.2, 128.0, 127.7,
116.91, 116.88, 104.17, 103.4, 82.4, 81.6, 80.1, 79.6, 77.7, 75.3, 74.8, 74.5,
74.4, 74.3, 74.1, 73.9, 72.3, 72.1, 71.8, 70.7, 68.6, 63.7, 51.4, 38.2, 30.2,
28.1 ppm; HRMS (ESI): m/z: calcd for C53H63N3O13Na: 972.4253
[M+Na]+; found: 972.4253.
Methyl 2,3,4-tri-O-benzyl-6-O-(2’,3’,4’-tri-O-benzyl-6’-O-levulinoyl-b-d-
glucopy ranosyl)-1-a-d-glucopyranoside (36): Synthesis of 36 was referred
to the general procedure of low-concentration 1,2-trans b-selective glyco-
sylation. 36 (162 mg, 83%) was obtained as white solid. [a]2D7 =+20.57
(c=1.03, in CHCl3); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.41–
7.32 (m, 25H; ArH), 7.28–7.24 (m, 5H; ArH), 5.06–4.77 (m, 9H), 4.74–
4.56 (m, 4H), 4.43–4.39 (m, 2H), 4.30 (dd, J=4.2, 12 Hz, 1H), 4.22 (d,
J=10.5 Hz, 1H), 4.07 (t, J=9.3 Hz, 1H), 3.90 (dd, J=3, 9.9 Hz, 1H),
3.77–3.69 (m, 2H), 3.63–3.51 (m, 5H), 3.41 (s, 3H), 2.78–2.73 (m, 2H;
CH2C=O), 2.63–2.58 (m, 2H; CH2C=O), 2.21 ppm (s, 3H; CH3C=O);
13C NMR (75 MHz, CDCl3, 258C): d=206.8, 173.0, 139.3, 138.8, 138.7,
138.6, 138.2, 128.95, 128.93, 128.88, 128.84, 128.81, 128.63, 128.58, 128.44,
128.40, 128.36, 128.32, 128.17, 128.10, 128.04, 104.2, 98.5, 85.2, 82.4, 80.2,
78.4, 77.9, 76.2, 76.1, 75.5, 75.4, 75.3, 73.8, 73.3, 70.2, 69.1, 63.7, 55.7, 38.3,
30.3, 30.2, 28.3 ppm; HRMS (ESI): m/z: calcd for C55H60O11Na: 994.4503
[M+Na]+; found: 994.4506.
2’,3’,4’-Tri-O-benzyl-6’-O-levulinoyl-a-d-galactopyranosyl Na-fluoren-9-yl
methoxycarbonyl-l-serine allyl ester (37a): Synthesis of 37a was per-
formed according to the general procedure of low-concentration 1,2-trans
b-selective glycosylation, but use only CH2Cl2 as reaction solvent. 37a
(128 mg, 75%) was obtained as colorless oil. [a]2D7 =+8.63 (c=0.90, in
CHCl3); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.80–7.78 (m, 2H;
ArH), 7.68–7.56 (m, 3H; ArH), 7.44–7.28 (m, 18H; ArH), 5.96–5.84 (m,
1H), 5.40–5.22 (m, 2H), 5.05–4.80 (m, 7H), 4.74–4.59 (m, 4H), 4.51–4.39
(m, 2H), 4.34–4.04 (m, 5H), 4.02–3.81 (m, 3H), 2.79–2.64 (m, 2H;
CH2C=O), 2.60–2.45 (m, 2H; CH2C=O), 2.16 ppm (s, 3H; CH3C=O);
13C NMR (75 MHz, CDCl3, 258C): d=207.1, 172.95, 170.2, 156.5, 144.3,
141.7, 139.0, 138.8, 138.6, 132.0, 128.89, 128.82, 128.74, 128.3, 128.2,
128.14, 128.09, 127.95, 127.87, 127.52, 125.62, 125.59, 125.29, 120.41,
119.21, 99.8, 78.99, 77.67, 76.70, 75.09, 73.79, 73.73, 70.53, 69.73, 67.57,
66.70, 66.63, 64.22, 55.1, 47.5, 38.25, 38.19, 30.29, 30.23, 28.1 ppm; HRMS
(ESI): m/z: calcd for C53H55NO12Na: 920.3616 [M+Na]+; found:
920.3609.
2’,3’,4’-Tri-O-benzyl-6’-O-levulinoyl-b-d-galactopyranosyl Na-fluoren-9-yl
methoxycarbonyl-l-serine allyl ester (37b): Synthesis of 37b was per-
formed according to the general procedure of low-concentration 1,2-trans
b-selective glycosylation. 37b (124 mg, 73%) was obtained as white solid.
[a]2D7 =+1.37 (c=0.85, in CHCl3); 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=7.80–7.77 (m, 2H; ArH), 7.62–7.57 (m, 2H; ArH), 7.47–7.25
(m, 19H; ArH), 5.99–5.87 (m, 2H), 5.37 (d, J=17.1 Hz, 1H), 5.25 (d, J=
10.5 Hz, 1H), 5.01 (d, J=11.7 Hz, 1H), 4.93 (d, J=10.8 Hz, 1H), 4.87–
4.78 (m, 3H), 4.73–4.57 (m, 4H), 4.49–4.11 (m, 7H), 3.95–3.85 (m, 3H),
3.61–3.54 (m, 3H), 2.77–2.73 (m, 2H; CH2C=O), 2.54–2.41 (m, 2H;
CH2C=O), 2.2 ppm (s, 3H; CH3C=O); 13C NMR (75 MHz, CDCl3, 258C):
d=206.97, 172.9, 170.1, 156.5, 144.36, 144.21, 141.66, 138.74, 138.62,
138.59, 131.94, 128.90, 128.86, 128.82, 128.77, 128.66, 128.22, 128.19,
128.13, 128.04, 127.55, 127.50, 125.74, 125.64, 120.36, 119.19, 104.8, 82.6,
79.3, 77.7, 75.8, 74.9, 73.61, 73.37, 72.6, 70.4, 67.7, 66.7, 63.4, 55.1, 47.5,
38.3, 30.3, 28.2 ppm; HRMS (ESI): m/z: calcd for C53H55NO12Na:
920.3616 [M+Na]+; found: 920.3619.
6-Chlorohexyl 2,3,4,6-tetra-O-benzyl-b-d-galactopyranoside (22): Synthe-
sis of 22 was referred to the general procedure of low-concentration 1,2-
trans b-selective glycosylation. 22 (140 mg, 85%) was obtained as colour-
less oily liquid. [a]2D7 =ꢀ4.24 (c=1.90, in CHCl3); 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=7.46–7.31 (m, 20H; ArH), 5.05–4.99 (m, 2H),
4.88–4.77 (m, 3H), 4.71 (d, J=11.7 Hz, 1H), 4.56–4.47 (m, 2H), 4.44 (d,
J=7.5 Hz, 1H), 4.06–4.03 (m, 1H), 3.98 (m, 1H), 3.90 (t, J=9 Hz, 1H),
3.69–3.53 (m, 7H), 1.85–1.72 (m, 4H; CH2), 1.52–1.45 ppm (m, 4H;
CH2); 13C NMR (75 MHz, CDCl3, 258C): d=139.3, 139.1, 139.0, 138.4,
128.9, 128.84, 128.75, 128.64, 128.50, 128.36, 128.01, 127.93, 104.4, 82.7,
80.1, 75.6, 74.96, 74.01, 73.98, 73.50, 70.22, 69.38, 45.50, 32.99, 30.06,
27.17, 25.96 ppm; HRMS (ESI): m/z: calcd for C40H47ClO6Na: 681.2953
[M+Na]+; found: 681.2953.
3-Chloropropyl 2,3-O-isopropylidene-4-O-(2’,3’,4’-tri-O-benzyl-6’-O-levu-
linoyl-b-d-galactopyranosyl)-a-l-rhamnopyranoside (33): Synthesis of 33
was performed according to the general procedure of low-concentration
1,2-trans b-selective glycosylation. 33 (114 mg, 65%) was obtained as
yellow oily liquid. [a]D27 =ꢀ16.32 (c=1.16, in CHCl3); 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=7.46–7.29 (m, 15H; ArH), 5.03–4.95
(m, 3H), 4.87–4.75 (m, 4H), 4.69 (d, J=11.7 Hz, 1H), 4.29–4.23 (m, 2H),
4.18–4.09 (m, 2H), 3.93–3.77 (m, 3H), 3.6–3.55 (m, 7H), 2.76–2.71 (m,
2H; CH2C=O), 2.51–2.47 (m, 2H; CH2C=O), 2.20 (s, 3H; CH3C=O),
2.11–2.03 (m, 2H; CH2), 1.55 (s, 6H; CH3C), 1.39–1.29 ppm (m, 7H);
13C NMR (75 MHz, CDCl3, 258C): d=206.9, 172.8, 139.4, 139.0, 138.8,
128.8, 128.72, 128.66, 128.62, 128.5, 128.1, 128.0, 127.9, 127.8, 109.6, 102.6,
97.4, 82.7, 79.99, 79.3, 18.6, 76.3, 75.5, 74.8, 73.94, 73.87, 72.43, 42.1, 38.3,
32.7, 30.3, 28.3, 28.1, 26.8, 18.3 ppm; HRMS (ESI): m/z: calcd for
C44H55ClO12Na: 833.3274 [M+Na]+; found: 833.3274.
Methyl 2,3,6-tri-O-benzyl-4-O-(2’,3’,4’-tri-O-benzyl-6’-O-levulinoyl-b-d-
galacto pyranosyl)-1-a-d-glucopyranoside (34): Synthesis of 34 was per-
formed according to the general procedure of low-concentration 1,2-trans
b-selective glycosylation. 34 (122 mg, 63%) was obtained as white solid.
[a]2D7 =+2.49 (c=0.98, in CHCl3); 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=7.47–7.22 (m, 30H; ArH), 5.06 (m, 2H), 4.88–4.77 (m, 5H),
4.75–4.59 (m, 5H), 4.37 (d, J=12 Hz, 1H), 4.31 (d, J=7.8 Hz, 1H), 4.12
(d, J=6.6 Hz, 1H), 3.99–3.70 (m, 6H), 3.65–3.52 (m, 3H), 3.47–3.32 (m,
5H), 2.73 (m, 2H; CH2C=O), 2.53–2.47 (m, 2H; CH2C=O), 2.19 ppm (s,
3H; CH3C=O); 13C NMR (75 MHz, CDCl3, 258C): d=206.9, 172.6, 139.7,
139.3, 139.1, 138.94, 138.93, 138.5, 128.92, 128.82, 128.81, 128.78, 128.67,
128.59, 128.52, 128.45, 128.41, 128.36, 128.20, 128.16, 128.06, 128.02,
127.91, 127.88, 127.82, 127.55, 103.05, 98.85, 82.79, 80.6, 80.3, 77.7, 76.9,
75.9, 75.6, 75.0, 73.7, 73.6, 73.2, 72.0, 70.4, 68.3, 63.1, 55.7, 38.3, 30.3,
28.3 ppm; HRMS (ESI): m/z: calcd for C60H66O13: 994.4503 [M]+; found:
994.4506.
3-Chloropropyl 2-O-benzyl-4,6-O-benzylidiene-3-O-(2’-azido-3’,4’,6’-tri-
O-benzyl ꢀ2’-deoxy-b-d-glucopyranosyl)-1-b-d-galactopyranoside (38):
Synthesis of 38 was referred to the general procedure of low-concentra-
tion 1,2-trans b-selective glycosylatin. 38 (126 mg, 77%) was obtained as
2-Azidoethyl 2,3-di-O-allyl-4-O-(2’,3’,4’-tri-O-benzyl-6’-O-levulinoyl-b-d-
galacto pyranosyl)-1-b-d-galactopyranoside (35): Synthesis of 35 was per-
formed according to the general procedure of low-concentration 1,2-trans
b-selective glycosylation. 35 (117 mg, 60%) was obtained as a yellow oily
liquid. [a]2D7 =ꢀ1.98 (c=0.74, in CHCl3); 1H NMR (300 MHz, CDCl3,
258C, TMS): d=7.50–7.48 (m, 2H; ArH), 7.38–7.28 (m, 18H; ArH),
5.97–5.86 (m, 2H), 5.39 (d, J=1.2 Hz, 1H), 5.24–5.02 (m, 5H), 4.88–4.85
(m, 2H), 4.78–4.74 (m, 2H), 4.65–4.53 (m, 3H), 4.37 (d, J=7.8 Hz, 1H),
4.25–3.99 (m, 8H), 3.87–3.67 (m, 5H), 3.64–3.37 (m, 7H), 2.75–2.70 (m,
2H; CH2C=O), 2.51–2.47 (m, 2H; CH2C=O), 2.19 ppm (s, 3H; CH3C=
O); 13C NMR (75 MHz, CDCl3, 258C): d=206.8, 172.8, 139.5, 139.1,
a
colorless oily liquid. [a]2D7 =+7.42 (c=1.22, in CHCl3); 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=7.64–7.61 (m, 2H; ArH), 7.53–7.51
(m, 2H; ArH), 7.46–7.35 (m, 19H; ArH), 7.28–7.21 (m, 2H; ArH), 5.60
(s, 1H; PhCH), 5.00–4.96 (m, 2H; vinyl-CH), 4.93–4.81 (m, 4H), 4.67–
4.53 (m, 3H), 4.47 (d, J=7.5 Hz, 1H), 4.36–4.33 (m, 2H), 4.17–3.98 (m,
3H), 3.9 (dd, J=3.3, 9.9 Hz, 1H), 3.82–3.57 (m, 7H), 3.48–3.40 (m, 3H),
2.18–2.09 ppm (m, 2H; CH2); 13C NMR (75 MHz, CDCl3, 258C): d=
138.9, 138.40, 138.38, 138.23, 129.13, 128.93, 128.88, 128.82, 128.78, 128.53,
128.47, 128.45, 128.39, 128.35, 128.25, 128.20, 126.7, 104.2, 103.2, 100.98,
Chem. Eur. J. 2009, 15, 10972 – 10982
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10979

K.-K. Tony Mong et al.
83.6, 78.96, 78.33, 38.21, 76.52, 75.94, 75.59, 75.56, 75.14, 73.88, 69.43,
69.30, 66.96, 66.77, 66.70, 42.35, 33.2 ppm; HRMS (ESI): m/z: calcd for
C50H54ClN3O10Na: 914.3395 [M+Na]+; found: 914.3390.
deacetylation, the mixture was neutralized with resin IR-120H+, filtered,
and concentrated for purification with column chromatography over
silica gel (elution:hexane/EtOAc/toluene=1/1/1) to furnish the disacchar-
ide 43 as white glassy solid (350 mg, 95%). [a]2D7 =+17.13 (c=0.78, in
6-Chlorohexyl 2,3,6-tri-O-benzyl-4-O-(2’,3’,6’-tri-O-benzyl-b-d-galactopyr-
anosyl)-1-b-d-glucopyranoside (39): Synthesis of 39 was prepared accord-
ing to the general procedure of low-concentration 1,2-trans b-selective
glycosylation. 39 (168 mg, 80%) was obtained as white glassy solid.
[a]2D7 =+15.23 (c=0.52, in CHCl3); 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=7.26–7.13 (m, 30H; ArH), 4.90 (d, J=10.8 Hz, 1H), 4.80 (d,
J=11.1 Hz, 1H), 4.70–4.55 (m, 6H), 4.47 (d, J=12.3 Hz, 1H), 4.39–4.27
(m, 5H), 3.94–3.81 (m, 3H), 3.74–3.22 (m, 14H), 2.36 (br, 1H), 1.70–1.55
(m, 4H; CH2), 1.37–1.30 ppm (m, 4H; CH2); 13C NMR (75 MHz, CDCl3,
258C): d=139.44, 139.00, 138.95, 138.65, 138.48, 138.25, 128.80, 128.71,
128.63, 128.61, 128.40, 128.27, 128.20, 128.13, 128.11, 128.01, 127.96,
127.89, 127.87, 127.81, 127.58, 103.93, 102.89, 83.22, 82.11, 81.43, 79.70,
77.60, 75.67, 75.57, 75.42, 75.25, 73.83, 73.45, 73.06, 72.33, 70.09, 68.76,
68.63, 66.46, 45.38, 32.84, 29.93, 27.01, 25.81 ppm; HRMS (FAB): m/z:
calcd for C60H69ClO11: 1000.4528 [M]+; found: 1000.4529.
1
CHCl3); H NMR (300 MHz, CDCl3, 258C, TMS): d=7.41–7.34 (m, 25H;
ArH), 7.28–7.22 (m, 5H; ArH), 5.06–4.93 (m, 4H), 4.90–4.80 (m, 5H),
4.76–4.67 (m, 4H), 4.57 (d, J=11.4 Hz, 1H), 4.45 (d, J=7.8 Hz, 1H), 4.17
(d, J=10.5 Hz, 1H), 4.06 (t, J=9.3 Hz, 1H), 3.92–3.85 (m, 2H), 3.79–3.50
(m, 8H), 3.42–3.40 ppm (m, 4H); 13C NMR (75 MHz, CDCl3, 258C): d=
139.2, 138.84, 138.76, 138.65, 138.54, 138.39, 128.96, 128.93, 128.86, 128.83,
128.62, 128.51, 128.46, 128.41, 128.35, 128.27, 128.10, 128.05, 104.2, 98.6,
85.0, 82.43, 82.41, 80.2, 78.2, 76.2, 75.56, 75,54, 75.42, 75.36, 73.84, 70.2,
69.1, 62.4, 55.7 pm; HRMS (ESI): m/z: calcd for C55H60O11Na: 919.4033
[M+Na]+; found: =919.4030.
Methyl 2,3,4-tri-O-benzyl-6-O-[2’,3’,4’-tri-O-benzyl-6’-O-(2”,3”,4”-tri-O-
benzyl-6-O-levulinoyl-b-d-glucopyranosyl)-b-d-glucopyranosyl]-1-b-d-
glucopyranoside (44): Disaccharide acceptor 43 (derived from 36 by
Zemplꢁn deacylation, 120 mg, 0.13 mmol), thioglucopyranoside
6
(105 mg, 0.16 mmol) and flame-dried MS (AW300, 300 mg) were sus-
pended in a 1:2:1 v/v CH2Cl2–CH3CN–EtCN (13 mL) solution under N2.
The resulting mixture was stirred at room temperature for 5 min and at
ꢀ708C for an additional 20 min, followed by addition of NIS (38 mg,
0.17 mmol) and TMSOTf (6 mL, 0.032 mmol). Upon completion of glyco-
sylation as monitored by TLC, saturated NaHCO3 (0.1 mL) and pieces of
Na2S2O3(s) were added to the mixture, followed by vigorously stirring at
room temperature until the deep-red color of the solution changed to
pale yellow. MS was then removed by filtration over celite, and the fil-
trate was dried (over MgSO4), filtered, and concentrated for flash-chro-
matography purification over silica gel (elution: hexane/CH2Cl2/EtOAc=
6:3:1) to furnish the desired trisaccharide 41 as colorless oily liquid
(134 mg, 70%). [a]2D7 =+16.92 (c=2.84, in CHCl3); 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=7.38–7.21 (m, 43H; ArH), 7.19–7.16 (m, 2H;
ArH), 5.08–4.75 (m, 16H), 4.74–4.45 (m, 9H), 4.39–4.12 (m, 6H), 4.00 (t,
J=9 Hz, 1H), 3.80–3.35 (m, 17H), 3.2 (s, 3H; OCH3), 2.75–2.70 (m, 2H;
CH2C=O), 2.62–2.56 (m, 2H; CH2C=O), 2.19 ppm (s, 3H; CH3C=O);
13C NMR (75 MHz, CDCl3, 258C): d=206.7, 172.96, 139.3, 138.86, 138.84,
138.77, 138.70, 138.57, 138.42, 138.27, 128.90, 128.86, 128.84, 128.80,
128.76, 128.58, 128.52, 128.44, 128.38, 128.34, 128.27, 128.14, 128.10,
128.08, 127.99, 127.96, 104.3, 103.9, 98.5, 85.2, 85.1, 82.4, 82.3, 80.0, 78.6,
78.2, 77.8, 77.7, 76.14, 76.09, 75.6, 75.42, 75.37, 75.23, 75.11, 73.75 73.26,
70.1, 69.0, 68.6, 63.7, 55.7, 38.2, 30.3, 28.3 ppm. HRMS (ESI): m/z: calcd
for C87H94O18Na: 1449.6332 [M+Na]+; found: =1449.6332.
6-Chlorohexyl 2,3,6-tri-O-benzyl-4-O-(3’-O-benzoyl-2’,6’-di-O-benzyl-b-d-
galactopyranosyl)-1-b-d-glucopyranoside (40): Synthesis of 40 was per-
formed according to the general procedure of low-concentration 1,2-trans
b-selective glycosylation. 40 (235 mg, 83%) was obtained as glassy solid.
[a]2D7 =ꢀ17.10 (c=0.74, in CHCl3); 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=7.90 (m, 2H; ArH), 7.44 (m, 3H; ArH), 7.30–7.18 (m, 19H;
ArH), 7.09–6.96 (m, 8H; ArH), 5.50 (d, J=3.0 Hz, 1H), 5.00 (d, J=
10.5 Hz, 1H), 4.83–4.45 (m, 8H), 4.38–4.30 (m, 3H), 4.13 (d, J=12.0 Hz,
1H), 3.96 (t, J=9.3 Hz, 1H), 3.88–3.85 (m, 1H), 3.76 (dd, J=3.6,
11.1 Hz, 1H), 3.69–3.64 (m, 2H), 3.58–3.32 (m, 10H), 2.45 (br, 1H), 1.66–
1.56 (m, 4H; CH2), 1.36–1.31 ppm (m, 4H; CH2); 13C NMR (75 MHz,
CDCl3, 258C): d=166.79, 139.36, 138.98, 138.54, 138.49, 138.11, 133.50,
130.19, 130.00, 128.78, 128.71, 128.63, 128.60, 128.37, 128.29, 128.23,
128.18, 128.15, 128.01, 127.98, 127.92, 127.87, 127.60, 103.99, 102.85, 83.14,
81.97, 80.49, 77.60, 77.04, 73.78, 73.51, 73.02, 72.65, 70.61, 70.12, 68.48,
67.75, 63.06, 45.36, 32.84, 30.03, 29.92, 27.00, 25.81, 25.39 ppm; HRMS
(FAB): m/z: calcd for C60H68ClO12
1015.4394.
: ; found:
1015.4399 [M+H]++
6-Chlorohexyl
2-azido-3,6-di-O-benzyl-2-deoxy-1-b-d-glucopyranoside
(41): Synthesis of 41 was performed according to the general procedure
of low-concentration 1,2-trans b-selective glycosylation. 41 (44 mg, 60%)
was obtained as colorless oil. [a]2D7 =ꢀ32.28 (c=0.3, in CHCl3); 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=7.43–7.29 (m, 10H; ArH), 4.96 (d, J=
11.4 Hz, 1H), 4.81 (d, J=11.4 Hz, 1H), 4.65 (dd, J=12.0, 4.8 Hz, 1H),
4.31 (d, J=7.8 Hz, 1H), 3.98–3.90 (m, 1H), 3.76 (d, J=6.6 Hz, 1H), 3.68–
3.52 (m, 4H), 3.46–3.29 (m, 2H), 3.26 (t, J=9.0 Hz, 1H), 2.72 (br, 1H),
1.83–1.76 (m, 2H; CH2), 1.72–1.64 (m, 2H; CH2), 1.51–1.43 ppm (m, 4H;
CH2); 13C NMR (75 MHz, CDCl3, 258C): d=138.5, 138.0, 129.0, 128.8,
128.5, 128.4, 128.2, 128.1, 102.6, 82.8, 75.4, 74.3, 74.1, 72.4, 70., 70.4, 66.1,
45.4, 32.9, 29.7, 27.0, 25.6 ppm; HRMS (FAB): m/z: calcd for
C26H35N3O5ClNa: 504.2260 [M+H]+; found: 504.2260.
6-Chlorohexyl 2,3,6-tri-O-benzyl-4-O-[2,3,6-tri-O-benzyl-4-O-(2,3-di-O-
benzyl-4,6 -O-di-tert-butylsilylidene-a-d-galactopyranosyl)-b-d-galacto-
pyranosyl]-1-b-d-glucopyranoside (46): Thiolactoside 23 (330 mg,
0.33 mmol), 6-chlorohexanol 13 (90 mg, 0.66 mmol), and flame-dried MS
(AW300, 400 mg) were suspended in a 1:2:1 v/v CH2Cl2–CH3CN–EtCN
(32 mL) solution at room temperature. The resulting mixture was stirred
at room temperature for 10 min and at ꢀ708C for additional 20 min, fol-
lowed by addition of NIS (77 mg, 0.34 mmol) and TMSOTf (12 mL,
0.066 mmol). Upon completion of glycosylation as judged by TLC, satu-
rated NaHCO3 (1 v/v% of reaction volume) and pieces of Na2S2O3(s)
were added to the reaction mixture, followed by vigorously stirring at
room temperatuer until the red color of the solution turned to pale
yellow. The resulting crude mixture was filtered over celite and diluted
with CH2Cl2 (40 mL). The CH2Cl2 solution was washed with H2O
(15 mL), brine (15 mL), dried (over MgSO4), filtered, concentrated, and
dried under vacuum for approximately 2 h. The resulting residue was dis-
solved in CH2Cl2 (5 mL), followed by addition of thiogalactopyranoside
45 (500 mg, 0.82 mmol) and flame-dried MS (AW300, 900 mg). The mix-
ture was stirred at room temperature for 15 min and at ꢀ108C for an ad-
ditional 20 min, followed by addition of NIS (1.88 mg, 0.83 mmol) and
TMSOTf (30 mL, 0.17 mmol). The mixture was stirred at ꢀ108C under N2
and the glycosylation reaction was monitored by TLC. Upon completion
of glycosylation as judged by TLC, saturated NaHCO3 (1 v/v% of reac-
tion volume) and small lumps of Na2S2O3(s) were added, followed by the
workup procedure described in the preparation of compound 44. The re-
sulting CH2Cl2 solution was concentrated for flash column chromatogra-
phy over silica gel (elution: hexane/CH2Cl2/EtOAc=7:2:1) to furnish
1,2:3,4-Di-O-isopropylidene-6-O-(2’,3’,4’,6’-tetra-O-benzyl-a-d-mannopyr-
anosy)-1-a-d-galactopyranose (42): Synthesis of 42 was performed ac-
cording to the general procedure of low-concentration 1,2-trans b-selec-
tive glycosylation. 42 (128 mg, 85%) was obtained as colorless oily liquid.
[a]2D7 =ꢀ46.11 (c=0.75, in CHCl3); 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=7.42–7.25 (m,18H; ArH), 7.19–7.16 (m, 2H; ArH), 5.55 (d, J=
5.1 Hz, 1H; H-1), 5.05 (d, J=1.8 Hz, 1H), 4.90 (d, J=10.5 Hz, 1H),
4.75–4.69 (m, 3H), 4.63–4.51 (m, 5H), 4.35 (dd, J=7.5, 5.1 Hz, 1H), 4.19
(dd, J=1.8, 8.1 Hz, 1H), 4.08–3.91 (m, 3H), 3.86–3.69 (m, 6H), 1.52 (s,
3H; CH3C), 1.45 (s, 3H; CH3C), 1.35 ppm (s, 6H; CH3C); 13C NMR
(75 MHz, CDCl3, 258C): d=138.9, 138.88, 138.82, 138.75, 128.7, 128.4,
128.2, 128.0, 127.98, 127.94, 127.88, 127.84, 109.7, 108.9, 97.6, 96.7, 80.4,
77.6, 75.5, 75.2, 74.9, 73.7, 72.7, 72.4, 71.3, 71.0, 70.9, 69.4, 65.7, 65.6, 26.5,
26.3, 25.3, 24.9 ppm; HRMS (ESI): m/z: calcd for C46H54O11Na: 805.3564
[M+Na]+, found: =805.3558.
Methyl 2,3,4-tri-O-benzyl-6-O-(2’,3’,4’-tri-O-benzyl-b-d-glucopyranosyl)-
1-a-d-glucopyranoside (43): Disaccharide 36 (410 mg, 0.4 mmol) in 1:2 v/v
CH2Cl2–MeOH solution (8 mL) was treated with a piece of freshly cut
sodium (approximately 10 mg) at room temperature. Upon completion of
10980
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Chem. Eur. J. 2009, 15, 10972 – 10982

Applications of Selective Glycosylation in Oligosaccharide Synthesis
FULL PAPER
target trisaccharide 46 as yellow oily liquid (248 mg, 75% from 23).
[a]2D7 =+46.47 (c=1.06, in CHCl3); 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=7.11–7.03 (m, 40H; ArH), 4.97 (d, J=11.4 Hz, 1H), 4.86 (d,
J=3.0 Hz, 1H), 4.80–4.14 (m, 19H), 4.02–3.62 (m, 11H), 3.54–3.14 (m,
10H), 1.64–1.53 (m, 4H; CH2), 1.33–1.32 (m, 4H; CH2), 0.91 (s, 9H;
tBu), 0.88 ppm (s, 9H; tBu); 13C NMR (75 MHz, CDCl3, 258C): d=
139.60, 139.43, 139.01, 138.98, 138.88, 138.83, 138.69, 138.54, 128.80,
128.72, 128.67, 128.63, 128.58, 128.49, 128.16, 128.07, 128.03, 127.97,
127.94, 127.85, 127.78, 127.66, 127.61, 127.56, 103.86, 100.33, 82.75, 82.05,
81.35, 79.31, 78.36, 77.60, 75.39, 75.22, 74.34, 73.98, 73.59, 73.51, 73.45,
73.40, 72.45, 71.33, 70.75, 70.06, 68.70, 67.88, 67.78, 67.40, 45.36, 32.83,
30.03, 29.91, 28.06, 27.96, 27.86, 27.75, 26.85, 27.65, 26.99, 25.80, 23.66,
21.00 ppm; HRMS (ESI): m/z: calcd C88H108ClO16Si: 1483.7095 [M+H]+;
found: =1483.7090.
tBu), 0.92 ppm (s, 9H; tBu); 13C NMR (75 MHz, CDCl3, 258C): d=
165.90, 139.41, 139.24, 138.95, 138.90, 138.66, 138.44, 138.12, 133.18,
130.25, 130.09, 128.73, 128.63, 128.58, 128.49, 128.34, 128.33, 128.25,
128.24, 128.17, 128.07, 128.01, 127.91, 127.87, 127.81, 127.80, 127.75,
127.61, 127.57, 127.33, 103.94, 103.10, 94.00, 83.11, 81.91, 79.71, 77.60,
77.31, 75.67, 75.49, 75.27, 73.85, 73.63, 73.58, 73.26, 72.79, 70.74, 70.51,
70.06, 68.62, 67.91, 67.09, 66.97, 66.19, 45.30, 32.80, 29.89, 27.91, 27.53,
26.96, 25.77, 23.62, 20.87 ppm; HRMS (ESI): m/z: calcd
C88H105ClNaO17Si: 1519.6707 [M+Na]+; found: 1519.6702.
6-Chlorohexyl 4-O-[3-O-(a-d-galactopyranosyl)-b-d-galactopyranosyl-1-
b-d-glucopyranoside, isoGb3 derivative (49): Protected isoGb3 48
(280 mg, 1.87 mmol) in a mixture of AcOH (95%, 0.25 mL) and THF
(5 mL) was treated with TBAF (1m in THF, 1.8 mL).[40] After stirring at
room temperature for 13 h, the mixture was diluted with CH2Cl2
(40 mL), washed with H2O (2ꢃ15 mL), dried over MgSO4, filtered, and
concentrated for the next debenzoylation. The resulting crude product
from desilylation (approximately 200 mg) was dissolved in 1:2 v/v
MeOH/THF (3 mL) and treated with 2n NaOH (2 mL), followed by stir-
ring at 608C for 36 h. Upon completion of benzoyl ester removal, the
mixture was diluted with CH2Cl2 (40 mL), and the solution was then
washed with 1n HCl (15 mL), H2O (15 mL), brine (15 mL), dried over
MgSO4, filtered, and concentrated for next hydrogenolysis. The crude
residue from debenzoylation step was dissolved in a mixture of formic
acid (0.35 mL) and MeOH (7 mL), followed by addition of 5% Pd/C
(100 mg). The mixture was stirred at room temperature under H2 for
16 h. Upon completion of hydrogenolysis as judged by TLC, Pd/C was re-
moved by filtration over celite, and the filtrate was concentrated for
column chromatography purification on C18 coated reverse phase silica
gel (Cosmosil 75C18-OPN; elution: H2O/MeOH gradient from 1:0 to
4:1) to furnish desired trisaccharide 49 as a colorless glassy solid (64 mg,
55% from 48). [a]2D7 =+53.00 (c=0.80, in MeOH); 1H NMR (300 MHz,
CD3OD, 258C): d=5.07 (s, 1H), 4.45 (d, J=6.6 Hz, 1H), 4.32 (d, J=
7.8 Hz, 1H), 4.24 (t, J=6.3 Hz, 1H), 4.07 (s, 1H), 3.96–3.53 (m, 18H),
3.44–3.42 (m, 1H), 3.34–3.32 (m, 1H), 3.27 (t, J=8.1 Hz, 1H), 1.84–1.75
(m, 2H; CH2), 1.71–1.62 (m, 2H; CH2), 1.48–1.43 ppm (m, 4H; CH2);
13C NMR (75 MHz, CD3OD, 258C): d=105.03, 104.16, 97.66, 80.99, 79.83,
76.57, 76.42, 76.35, 74.67, 72.22, 71.30, 71.08, 70.98, 70.73, 70.11, 66.60,
62.71, 62.42, 61.96, 45.71, 33.71, 30.56, 27.69, 26.32 ppm; HRMS (ESI):
m/z: calcd C24H43ClO16Na: 645.2132 [M+Na]+; found: 645.2132.
6-Chlorohexyl 4-O-[4-O-(a-d-galactopyranosyl)-b-d-galactopyranosyl]-1-
b-d-glucopyranoside, Gb3 derivative (47): Protected Gb3 46 (270 mg,
1.82 mmol) dissolved in a mixture of AcOH (95%, 0.25 mL) and THF
(5 mL) was treated with tetrabutylammonium fluoride (TBAF; 1m in
THF, 1.8 mL).[40] After stirring at room temperature for 13 h, the reaction
was diluted with CH2Cl2 (40 mL), which was washed with H2O (2ꢃ
15 mL), dried (over MgSO4), filtered, and concentrated for the next hy-
drogenolysis. The resulting residue from desilylation (approximately
200 mg) was dissolved in a mixture of formic acid (0.35 mL) and MeOH
(7 mL) and treated with 5% Pd/C (100 mg). The reaction mixture was
stirred at room temperature under H2 for 14 h. Upon completion of hy-
drogenolysis as judged by TLC, Pd/C was removed by filtration over
celite, and the filtrate was concentrated for column chromatography pu-
rification on C18 coated reverse-phase gel (Cosmosil 75C18-OPN) (elu-
tion: H2O/MeOH gradient from 1:0 to 4:1) to furnish desired trisacchar-
ide 47 as white glassy solid (67 mg, 60% from 46). [a]2D7 =+33.5 (c=
0.20, in MeOH); 1H NMR (300 MHz, CD3OD, 258C): d=4.90 (d, J=
3.9 Hz, 1H), 4.45 (t, J=8.3 Hz, 2H), 4.32 (t, J=6.5 Hz, 1H), 3.99–3.50
(m, 20H), 3.25 (t, J=8.4 Hz, 1H), 1.79–1.70 (m, 2H; CH2), 1.65–1.56 (m,
2H; CH2), 1.46–1.35 ppm (m, 4H, CH2); 13C NMR (75 MHz, CD3OD,
258C): d=103.56, 102.28, 100.60, 78.89, 77.62, 75.73, 75.10, 74.23, 72.43,
71.19, 71.09, 70.84, 69.62, 69.20, 68.85, 60.76, 60.67, 60.32, 45.93, 32.07,
28.87, 26.09, 24.62 ppm; HRMS (ESI): m/z: calcd C24H43ClNaO16
:
645.2132 [M+Na]+; found: =645.2132.
6-Chlorohexyl 2,3,6-tri-O-benzyl-4-O-[2,6-di-O-benzyl-4-O-benzoyl-3-O-
(2,3-di-O-benzyl-4,6-O-di-tert-butylsilylidene-a-d-galactopyranosyl)-b-d-
galactopyranosyl]-1-b-d-glucopyranoside (48): A mixture of thiolactoside
24 (280 mg, 0.28 mmol), 6-chlorohexanol 13 (76 mg, 0.56 mmol) and
flame-dried MS (AW300, 330 mg) were suspended in 1:2:1 CH2Cl2–
MeCN–EtCN (28 mL) at room temperature under N2. The mixture was
stirred at room temperature for 10 min under N2 and at ꢀ708C for addi-
tional 20 min, followed by addition of NIS (67 mg, 0.29 mmol) and
TMSOTf (10 mL, 0.056 mmol). Upon completion of glycosylation, satu-
rated NaHCO3 (1 v/v% of reaction volume) and small lumps of
Na2S2O3(s) were added to the reaction mixture, followed by the workup
procedure as described in the preparation of compound 44. The crude
residue obtained was dried under vacuum for aproximately 2 h and made
ready for next glycosylation. The crude residue from the previous step
was then dissolved in CH2Cl2 (4 mL), to which thiogalactopyranoside 45
(436 mg, 0.72 mmol) and flame-dried MS (AW300, 700 mg) were added
under N2. The resulting mixture was stirred at ꢀ108C for 20 min, and
then followed by addition of NIS (180 mg, 0.79 mmol) and TMSOTf
(29 mL, 0.16 mmol). Upon completion of glycosylation as judged by TLC,
saturated NaHCO3 and small lumps of Na2S2O3(s) were added and then
the workup procedure as described in the preparation of compound 44
was performed. The crude residue was purified by flash column chroma-
tography over silica gel (elution: hexane/CH2Cl2/EtOAc=15:5:1) to fur-
nish expected trisaccharide 48 as yellow oily liquid (292 mg, 70%).
[a]2D7 =+56.13 (c=0.62, in CHCl3); 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=7.95 (d, J=7.2 Hz, 2H; ArH), 7.46 (t, J=7.5 Hz, 1H; ArH),
7.35–7.19 (m, 29H; ArH), 7.14–7.08 (m, 6H; ArH), 7.04–7.00 (m, 2H;
ArH), 5.81 (d, J=2.7 Hz, 1H), 5.28 (d, J=3.3 Hz, 1H), 5.09 (d, J=
10.8 Hz, 1H), 4.93–4.60 (m, 8H), 4.55–4.36 (m, 8H), 4.24 (d, J=12.0 Hz,
1H), 4.11–4.07 (m, 1H), 3.97–3.83 (m, 6H), 3.73–3.59 (m, 6H), 3.49–3.37
(m, 6H), 1.74–1.65 (m, 4H; CH2), 1.43–1.41 (m, 4H; CH2), 0.95 (s, 9H;
Acknowledgements
We thank the National Science Council, Taiwan for financial support
(Grant no. 96–2113m-009–016), and Ms. C.-C. Chang of NCTU for low-
temperature NMR studies.
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Received: April 28, 2009
Published online: September 11, 2009
10982
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Chem. Eur. J. 2009, 15, 10972 – 10982